ABSTRACT Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy, drugs such as trastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses and increased disease-free survival in patients with metastatic disease. However, despite an initial positive response, the majority of patient?s exhibit resistance - rendering the therapy ineffective within one year of treatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) and its associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in this de novo and acquired resistance. Therefore, identification of novel targets and antineoplastic agents that modulate IGF-1R signaling is paramount. We have recently identified soluble E-cadherin, termed sEcad, as a novel oncogenic target that is selectively increased in human breast cancers. Additionally, we have discovered that sEcad imparts its tumorigenic effects (enhances proliferation, migration and invasion) by activating many of these resistance pathways, including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly, using a purified IGF-1R holoreceptor, we are the first to discover that sEcad acts as a true ligand for IGF-1R and in the presence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore, we have evidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands, IGF1 and EGF, to promote cancer cell proliferation, migration and invasion in vitro and act as an oncogenic driver in xenograft tumors in vivo. Therefore, we propose that sEcad is a valid and innovative therapeutic target for breast cancer. Additionally, we have recently tested region-specific antibodies against sEcad that successfully suppressed HER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis and necrosis), via down-regulating the IGF-1R, HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumab? resistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice, our studies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibiting proliferation and inducing cell death. Consistent with the in vivo findings, this targeted therapy inhibited proliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumab? resistant breast cancer cells, without showing any off-target cytotoxic effects in normal cells. In this translational study, we have assembled an outstanding research team to: 1) biochemically and biophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcad suppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how the antibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy, PK/PD studies and evaluation of off-target effects. Of note, although monoclonal antibodies against IGF-1R have given mixed results in clinical trials, these anti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors, with a very unique and innovative targeting mechanism.